Belle and Abby Andrews have been traveling every two weeks to Chicago for experimental Niemann-Pick medication

Dressed in white spring dresses and hair pulled back in white bows, Belle and Abby Andrews look like angels.

“I’m getting big,” 6-year-old Belle says as her parents, Pam and Chris Andrews, talk about her moving up to a different classroom in the fall. “I’m going to a new class.”

In the family’s Southwest Austin home in late May, Belle’s 2-year-old sister, Abby, is busy doing what 2-year-olds do: putting crayons and markers to her mouth as the family draws pictures of bluebonnets at Belle’s request.

They call them Belle bonnets because Belle was born in spring just as the bluebonnets were coming up.

In March, she had a birthday any 6-year-old would want, full of Disney princesses. Under the celebration, though, it was a time of heartbreak and uncertainty for the family.

Just eight days before, Belle was diagnosed with Niemann-Pick Type C1, a rare genetic disorder sometimes called childhood Alzheimer’s. Nineteen days after the diagnosis, Abby also was diagnosed. Their parents did not know they both carried an autosomal recessive gene that both girls inherited.

The girls’ diagnoses took the family from a doctor’s office in Austin to Rush University Medical Center in Chicago to the National Institutes of Health in Washington, D.C. Soon they will be able to get treatment back home in Austin at Dell Children’s Medical Center of Central Texas.

After Thanksgiving, the girls will have the every-two-week treatment administered in a room at Dell Children’s when Dell becomes a site for a promising international study that is testing the efficacy of a new drug specifically for this disorder.

It is something for which the family is truly thankful.

Getting the diagnosis

Pam Andrews, 44, had mother’s intuition, often dismissed, that something wasn’t right with Belle.

When Belle was playing on the playground at age 3, Pam noticed other kids weren’t falling like Belle was. She was falling as much as six times a day. By the time she was 4, she had broken her nose twice.

Pam started noticing how Belle walked in an awkward way. When she was 4, Belle returned to a gymnastics class after summer break, and the other kids had improved on the balance beam. Belle had not.

“It was the first time I said to Pam, ‘I think there is something,’” Chris Andrews, 45, says.

Someone at Belle’s school said something about her gait, too. The Andrewses went to a pediatric orthopedic specialist, who ruled out hip dysplasia. “They looked at her and nothing was wrong,” Chris says. “Maybe she’s just clumsy; some people are clumsy.”

But Niemann-Pick is “insidious and really subtle,” Pam says.

When she was 4, it wasn’t just that she was falling. Belle’s fine motor skills were affected, too. She wrote with a shaky hand.

Mary Elizabeth Parker, Belle’s physical therapist, encouraged the Andrewses to continue to seek answers. They went to a neurologist, and he ruled out many disorders including muscular dystrophy and cerebral palsy.

An MRI showed that everything was normal.

Other things continued to show up. Her spleen was enlarged and she had a low white blood cell count, yet the only illnesses she had had were two stomach viruses and some ear infections.

Two years ago, genetic testing for specific biomarkers was done. Nothing showed up.

The family went to at least eight different specialists, and no one found anything. Doctors didn’t know what they were looking for and didn’t know what tests to run.

Belle’s symptoms and the Andrewses’ questions persisted.

“As a mom, you know something is wrong,” Pam says.

At her 5-year-old well check, Belle didn’t see their regular pediatrician. Instead they saw Dr. Amy White, another physician in the practice. She talked with Pam, looked at some of the previous lab results, felt Belle’s spleen and thought, “There’s a lot of things that don’t make sense,” White says.

She along with physical therapist Parker encouraged the Andrewses to go back to neurology and to genetics to see if there was something more to test for. White says she studied Niemann-Pick in medical school but had never cared for a child with it. “Because we know it is so rare, it didn’t pop into my mind at first,” White says.

Niemann-Pick is estimated to occur in childhood in 1 in 100,000 births, and that’s a best guess using data from France. “We don’t really know in the U.S.” says Dr. Forbes Porter, a senior investigator at the NIH who has been studying NPC1 for 10 years. “There’s no repository, no centralized database.”

The Andrewses made an appointment to see geneticist Dr. James Gibson in March 2015 for the first available appointment, which wasn’t until November.

The Andrewses almost canceled that appointment because Belle was doing well in her therapies and demonstrating few symptoms.

“With genetic testing, we were thinking we were opening a can of worms,” Pam says. “Let’s forget it. No one in our family has a rare disease.” They were scared and secretly hoping everything was OK.

They kept the appointment and fought with insurance representatives because the whole exome sequence test is expensive and required both Belle and her parents to be tested. Insurance came through.

Finally, on March 10, Gibson gave the results to them: Niemann-Pick Type C1.

Understanding the diagnosis

NPC1 is a lysosomal storage disease. Lysosomes are sacks of enzymes within cells that are like the recycling centers. They break up large molecules, then pass on the fragments to the rest of the body to break them down or send them back into the cell to perform their functions. In NPC1, cholesterol in brain cells cannot be moved to where it needs to go. This damages brain cells, which eventually die.

Children who have NPC1 usually experience clumsiness, shakiness of the hands and poor fine motor skills; problems with short-term memory, thinking and learning skills; hearing loss; problems swallowing; and trouble looking up with their eyes. They also might have seizures and eventually lose the ability to do school work, talk and walk.

Like many diseases, NPC1 has a spectrum, Porter says. Researchers know that the earlier the onset of neurological symptoms, the earlier kids die, he says. From diagnosis to death is about 10 to 15 years, but children who have seizures tend to have more problems and die earlier, Porter says.

“There are always exceptions, but in children it is invariably a lethal disorder,” he says.

There is also adult-onset NPC1, which might start with psychiatric problems or be confused with Alzheimer’s disease or mood disorders. Porter says he believes adult-onset NPC1 might be more common than the 1 in 100,000 rate identified with childhood-onset NPC1.

At the appointment with Dr. Gibson, the Andrewses were given some information about the disorder and encouraged to call Make-A-Wish.

“For the first 90 days, it was really a feeling of despair and grief,” Pam says. “I was terrified. I thought of it as a death sentence for our kids.”

The evening after the diagnosis, after the girls were asleep, Pam and Chris called another family they found online who had children with NPC1. They found out about a new, promising drug and a clinical study that was going on at the NIH and at Rush Medical Center in Chicago with Dr. Elizabeth Berry-Kravis.

Friends and family set up a Facebook page and a Saving Belle GoFundMe account to keep loved ones informed and to have a way to support the family. The Andrewses didn’t know how expensive this diagnoses would be, but they knew it would be costly. They initially asked for $200,000.

After Belle was diagnosed, doctors immediately tested Abby, who wasn’t showing any symptoms except that she had been late to crawl and late to walk; that was attributed to her being born two months early. When those results came back on March 29, it was another devastating blow.

Pam and Chris Andrews didn’t believe it would be both girls. Genetics predicted only a 25 percent chance of either girl having it. Yet, they both did.

The Saving Belle Facebook page and GoFundMe account changed to Saving Belle and Abby. Organizers asked for $350,000 and have raised more than $195,000.

“We are filled with gratitude every day for those that have supported us in this journey,” the Andrewses say in an email.

Finding hope

By the end of March, the Andrewses headed to Chicago to meet with Berry-Kravis, who after years of specializing in rare genetic disorders, particularly Fragile X syndrome, was working as co-principal investigator on an NPC1 study to test a formula of the molecule hydroxypropyl-beta-cyclodextrin — called VTS-270 — and its ability to stop the progression of NPC1. VTS-270 is manufactured by Vtesse, a new drug company that licensed this particular form of hydroxypropyl-beta-cyclodextrin from the NIH in 2015 to bring this drug to market for NPC1 patients.

“There was no treatment for the children in the USA,” Vtesse CEO Dr. Ben Machielse says about children with NPC1. “It’s an opportunity to help the children, as ultra-rare diseases do not get a lot of attention. At Vtesse, we hope to use our drug development experience to find and secure regulatory approval of new treatments for diseases like this.”

At that appointment, Berry-Kravis pre-screened Belle for the trial.

In April, the Andrews family also went to the NIH for further testing and to become part of a natural history study on NPC1 that Porter is doing. That study is tracking the progression of the disease.

For three days at the NIH, both girls were tested to chart disease progression based on nine domains: ambulation, speech, swallowing, fine motor skills, cognition, seizures, memory, hearing and eye movement. In addition to the enlarged spleen and liver, the telltale sign of NPC is vertical gaze palsy, an inability to move their eyes up and down without moving their heads. Instead their eyes will go in a circular motion to get to the up position or will not go up at all.

The NIH results found that Abby was minimally affected and Belle was mildly affected by the disease.

They also learned more about the progression of the disorder. “We’re very lucky that we caught this disease early,” Pam Andrews says.

The VTS-270 study already had completed the first phase. Patients in that phase received the drug once a month through a lumbar puncture. The theory is that VTS-270 “promotes the transport of cholesterol out of the cell,” Machielse says. The body can get rid of it and it won’t build up in brain cells.

Researchers have been enrolling the next phase of the study, which is designed to need 51 patients to be able to measure an effect with statistical significance. In this phase, dosing would be every two weeks because that schedule has been shown to be more effective in cats. Also different: The first phase was considered open label, in which every study participant received the drug in an effort to test the dosing level. This new phase is a blind study. One-third of the participants are getting a sham procedure instead of VTS-270 to prove that it’s the VTS-270 that is causing the positive effects and not something else.

Belle qualified for the study. Abby did not.

For Belle to be in the study, the Andrewses would have to bring her to a trial site every two weeks for a year and would not know whether she was receiving the drug. After that year was up, she would be guaranteed that she would be getting the drug.

Even though Abby didn’t meet the eligibility requirements to be in the study, she could be given VTS-270 based on a protocol Berry-Kravis had written that was approved by the FDA under a process called expanded access, which also is called compassionate use.

The Andrewses decided to enroll Belle in the study and get Abby on VTS-270 based on expanded access. It was a chance to not have the disease progress.

“We’re buying time until something else can come along and cure this,” Chris Andrews says.

The Andrewses chose Rush Medical Center in Chicago over other trial sites including Boston, Sacramento and Baltimore because it is where Berry-Kravis is and had the most direct flights from Austin. It would mean flying to Chicago every two weeks on a Sunday afternoon, checking into a hotel and grabbing dinner. Then off to bed before spending the next day at the hospital where the girls get their lumbar punctures and any other tests that need to be done before flying home. The girls would need rest the day after. It would mean three-day school weeks every other week. And for the Andrewses, it would mean time away from work — he’s a lawyer; she’s a director at a consulting company.

Abby received her first dose of VTS-270 on May 20, and Belle was given either VTS-270 or a sham procedure. They won’t know which she’s receiving until the trial gets to 51 people and those 51 have been in the study for a year. The trial has more than 30 participants right now, with more being added each month.

Because of the study rules, they cannot talk about what changes they have seen in their daughters.

Coming home

For six months, they have dutifully gone to Chicago every two weeks. They estimate they are spending $10,000 a month in travel expenses and other medical expenses. Vtesse pays for the travel of Belle and one adult, and the Andrewses pay for Abby and another adult.

On her Facebook page, Pam Andrews shared early into the girls’ diagnoses that her dream was to open up a trial site in Austin. When they were at the NIH in April, she also asked her mother and sister to call friends to talk to people they knew at Dell and Seton.

The Andrewses knew that it would make sense for Vtesse to have a site in the Southwest.

They kept telling Dell, “If you build it, we will come,” Pam Andrews says. They knew that if there were any NPC1 kids around Texas they would be within driving distance of treatment.

Two of them, 16-year-old Kayla and 20-year-old Cody Ruthven, live in Blue near Elgin and have been traveling to the NIH once a month since January 2014. They are part of the first phase of the clinical trial.

When Cody was 3, he had an enlarged spleen and abnormal cells in his bone marrow but no diagnosis. When Kayla was born, she also had an enlarged spleen.

In the fourth grade, Cody started struggling in school. In middle school, his parents were told he had attention deficit disorder. His parents also noticed he ran a little differently than other kids when he played baseball. And when he held a glass, he would shake.

When he was in eighth grade, he saw an ophthalmologist at Vanderbilt University in Nashville, Tenn., where the family was living at the time. “He noticed that his eyes wouldn’t roll down,” says mother Dena Ruthven. “We didn’t think anything of it. We had already known that. We just thought, ‘Oh, well, that’s just the way our kids were.’ As soon as he saw that, he said, ‘Let me check sister.’” It was the same thing for Kayla.

The Ruthvens were sent to a genetic neurologist, who made the diagnosis. The Ruthvens knew what NPC1 was because dad Scott Ruthven had a first cousin who died from it. Like the Andrewses, the Ruthvens headed to NIH to see Porter to become part of the natural study.

Once they moved to Blue and became part of the first phase of the VTS-270 study, the Ruthvens gave the name of their neurologist in Austin to Vtesse in the hope that they could get the study moved to Dell, but nothing happened.

Then they heard about the Andrews children and Pam Andrews’ quest. “Pam put a little more fire up their butt,” Dena Ruthvens says. “When Pam got going, she really got going. I’m thankful for that.”

Machielse agrees. “People like Pam and Chris make a big difference,” he says.

When Dell begins participating in the clinical trial after Thanksgiving, the hospital will start with six kids: Belle and Abby, Cody and Kayla, and two other children from two separate families.

As Dell has space available, they will enroll more children. “We don’t think we’ll have any capacity issues,” says Dr. Mark Shen, president of Dell Children’s.

Shen says Dell has a lot of different research studies happening, including other international studies on rare disorders. For Dell, it took a while to get the right people in place to do the study here. Gibson will oversee the study at Dell and a research coordinator has been hired.

Dell has to agree to follow the study exactly as the other sites are doing it, and when those protocols were amended, Dell had to sign new agreements before it could start. Now all agreements are signed and the families are ready to go.

“There’s a lot more detail when it’s a super-rare disease and a smaller number of children,” Shen says.

Clinical trials like these involve a lot of time and paperwork, Berry-Kravis says. “Sometimes, it’s daunting.”

While Dell is not the fastest new site to open, it is faster than most, Machielse says. Vtesse started talking to Dell in June and it usually takes a year to get a site active, he says. “It’s very fast.”

“Dell has highly qualified staff, which is needed for this study,” he says. “It’s a very complex study because of the assessments.”

Because Belle started her assessments in Chicago, she will have them done there every two months. One treatment out of every four will be in Chicago with the assessments; the other three will be at Dell. After the year is over, the Andrewses can do all their treatments at Dell and return to the NIH once a year for the natural history study.

On the horizon

The VTS-270 study has been given breakthrough status by the FDA, which means that researchers can share with the FDA what they are learning as it happens rather than waiting until the study is done.

The study looks to be continuing through 2017, which means that both Abby and Belle will have access to VTS-270 through then.

You don’t want to even guess how long it will be before it gets approved by the FDA, Porter says. “If we start to build up expectation and something interferes and it doesn’t happen, or something delays it, you don’t want to disappoint families or give them false hope.”

“We’re optimistic, based on our data, that cyclodextrin (VTS-270) will play a role,” he says.

He knows that it won’t be VTS-270 alone. “It will likely have to be a combination of drugs,” he says. Some drugs might work for one symptom, others for another.

What VTS-270 and the other drugs being developed won’t do is reverse the effects of the disease. “The goals is really to halt or slow the neurological progression,” Porter says. “It would be fantastic to have something to slow it down.”

A cell that is lost is gone forever, but there is hope that dysfunctioning cells can be cleared out and functioning again, he says. Something like stem cell replacement would be needed to reverse damage already done, Porter says. “That’s the only thing on the horizon that could be used to replace the cells that have been lost,” he says. Researchers are working on that with other disorders.

Porter also has been working on a blood test for NPC1 with Washington University. They have one developed, but more work needs to be done, he says.

A blood test would make it possible to have NPC1 be part of a newborn screening. That’s one of the Andrewses’ goals. Belle and Abby have inspired them to create a foundation, the Firefly Fund, to support research and education to accelerate a cure for rare and fatal childhood neurodegenerative diseases. The fund will launch on Feb. 28 at Studio 6A on the University of Texas campus, where “Austin City Limits” used to be taped.

The advantage, says Porter, would be earlier interventions on symptoms. Belle now has orthotics to help her walk and hearing aids. She also has five therapists who work on speech, occupational therapy, physical therapy, reading and vision. “Families wouldn’t have to go through the diagnostic odyssey the Andrewses did,” Porter says. “Right now it takes four to five years from the first symptom to getting the diagnosis.”

For Belle, that journey means that cells already have died.

“She’s very aware that other people don’t have limitations with their bodies,” Pam Andrews says. “That’s hard for me to watch as a mom.”

The Andrewses have decided to give age-appropriate information about the disorder to Belle and Abby. Belle knows that she goes to Chicago to see Berry-Kravis “because I fall down,” she says.

The girls find comfort in going through this together. “They have each other, and that has proven to be a real blessing,” Pam Andrews writes.

Right now, the Andrewses have a lot more hope than they did in March. In June, they went to the Ara Parseghian Medical Research Foundation’s conference in Tucson. There they met Cindy Parseghian, daughter-in-law of the former Notre Dame football coach. She lost three of her four kids to Niemann-Pick. “She had a lot of grace and humility,” Pam Andrews says. “And she carries around a lot of pain, and she carries that pain in the utmost graceful way.

“Before, I was full of hopelessness, despair and pain. I left there really changed,” she says. “I left there feeling full of hope rather than despair. That’s not to say I don’t have moments of the day, but my kids are happy. They don’t live in despair.”

About the Author

NICOLE VILLALPANDO
Nicole Villalpando writes about families in Raising Austin and is the editor of Season for Caring.

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